Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
Nanoscale. 2011 Oct 5;3(10):4314-22. doi: 10.1039/c1nr10580a. Epub 2011 Sep 5.
Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC(50) of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.
多药耐药性（MDR）是癌症化疗成功的主要障碍之一。克服 MDR 的一种有效方法是使用纳米颗粒介导的药物输送来增加耐药性癌细胞中药物的积累。在这项工作中，我们首先报告了一种基于介孔硅纳米粒子（MSNs）负载阿霉素（DMNs）的无机工程递药系统克服 MCF-7/ADR（一种 DOX 耐药且 P-糖蛋白（P-gp）过表达的癌细胞系）多药耐药性的性能和机制。实验结果表明，DMNs 可以增强阿霉素（DOX）的细胞摄取，并增加 DOX 对 MCF-7/ADR 细胞的增殖抑制作用。DMNs 对 MCF-7/ADR 细胞的 IC50 比游离 DOX 低 8 倍。然而，在 DMNs 对 MCF-7 细胞（一种 DOX 敏感的癌细胞系）中并没有发现 DOX 的改善作用。通过共聚焦激光扫描显微镜证实了 DMNs 在 MCF-7/ADR 细胞中增加了 DOX 的细胞内摄取和核积累，这可能是由于 P-gp 的下调和 MSNs 本身绕过了外排作用。DMNs 的细胞摄取机制表明，巨胞饮作用是 MCF-7/ADR 细胞摄取 DMNs 的途径之一。体内分布研究表明，DMNs 诱导 DOX 在耐药肿瘤中的积累高于游离 DOX。这些结果表明 MSNs 可以作为克服多药耐药性的有效递药系统。
